U.S. patent number 4,018,889 [Application Number 05/646,295] was granted by the patent office on 1977-04-19 for oxytetracycline compositions.
This patent grant is currently assigned to Pfizer Inc.. Invention is credited to William W. Armstrong.
United States Patent |
4,018,889 |
Armstrong |
April 19, 1977 |
**Please see images for:
( Certificate of Correction ) ** |
Oxytetracycline compositions
Abstract
Oxytetracycline aqueous solutions containing 2-pyrrolidone as a
co-solvent suitable for pharmaceutical use and especially useful
for either oral, topical or parenteral administration are
disclosed.
Inventors: |
Armstrong; William W. (Mill
Neck, NY) |
Assignee: |
Pfizer Inc. (New York,
NY)
|
Family
ID: |
27164830 |
Appl.
No.: |
05/646,295 |
Filed: |
January 2, 1976 |
Current U.S.
Class: |
514/152 |
Current CPC
Class: |
A61P
31/00 (20180101); A61K 47/02 (20130101); A61K
31/65 (20130101); A61K 47/22 (20130101); A61K
9/0014 (20130101); A61K 9/0019 (20130101) |
Current International
Class: |
A61K
47/22 (20060101); A61K 31/65 (20060101); A61K
47/02 (20060101); A61K 031/79 (); A61K
031/65 () |
Field of
Search: |
;424/227,80 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
825,656 |
|
1975 |
|
BE |
|
2,258,187 |
|
Jan 1975 |
|
FR |
|
1,091,287 |
|
Apr 1961 |
|
DT |
|
805,026 |
|
Feb 1957 |
|
UK |
|
802,111 |
|
Sep 1956 |
|
UK |
|
Other References
Japanese Patent Application Publication No. SHO 47-303, (Jan. 6,
1972). .
Japanese Patent Application Publication No. SHO 43-1758, (Jan. 22,
1968). .
E. H. Gans & T. Higuchi, J. Pharm. Sci; 46, p. 458
(1957)..
|
Primary Examiner: Meyers; Albert T.
Assistant Examiner: Stephens; Daren M.
Attorney, Agent or Firm: Murphy; Francis X. Knuth; Charles
J. Spiegel; Allen J.
Claims
What is claimed is:
1. An oxytetracycline composition comprising a solution in water of
from about 1 to 40% by weight of an antibiotic compound selected
from the group consisting of oxytetracycline and the
pharmaceutically acceptable acid addition salts thereof, from about
0.8 to 1.3 molar proportion of a pharmaceutically acceptable
magnesium compound soluble in said solution, and from about 10 to
50% by weight of 2-pyrrolidone, said composition having a pH value
in the range of from about 7.5 to 9.5.
2. A composition as claimed in claim 1 wherein said antibiotic
compound is oxytetracycline.
3. A composition as claimed in claim 1 wherein said magnesium
compound is introduced in the form of magnesium oxide.
4. A composition of Claim 1 wherein polyvinylpyrrolidone having an
average molecular weight of between about 5,000 and 100,000 is also
present in a concentration of from about 1 to 7% by weight of the
total.
5. A composition as claimed in claim 1 wherein said antibiotic
compound is present at a level of from about 10 to 40% by
weight.
6. A composition as claimed in claim 1 wherein said antibiotic
compound is present at a level of from about 20 to 30% by
weight.
7. A composition as claimed in claim 1 having a pH value of from
about 8.5 to 9.
8. An oxytetracycline composition comprising a solution in water of
from about 20 to 30% by weight of oxytetracycline, from about 0.8
to 1.3 molar proportion of a pharmaceutically acceptable magnesium
compound soluble in said solution, from about 10 to 50% by weight
of 2-pyrrolidone and from about 1 to 7% by weight of
polyvinylpyrrolidone, said composition having a pH value in the
range of from about 8.5 to 9.
Description
BACKGROUND OF THE INVENTION
This invention relates to antibiotic compositions suitable for
pharmaceutical use. More particularly, it relates to aqueous
oxytetracycline solutions containing 2-pyrrolidone.
Previous efforts made to prepare compositions suitable for topical
or parenteral administration which contain more than 200 mg./ml.
have been unsuccessful. This is of particular importance in the
case of veterinary oxytetracycline parenteral compositions in which
high doses are required.
U.S. Pat. No. 2,980,584 discloses aqueous parenteral solutions of
oxytetracycline metal complexes containing 25-80% of an acetic or
lactic acid carboxamide, such as N,N-dimethylacetamide and
N-(.beta.-hydroxyethyl) lactamide at a pH of 8.5-9.5.
Concentrations of 10 to 100 mg./ml. are disclosed.
U.S. Pat. No. 2,990,331 discloses parenteral solutions of
oxytetracycline hydrochloride, containing about 50 mg./ml. having a
pH value between 5 and 7, containing magnesium ions, an alkali
bisulfite and a carboxylic acid amide, such as lactic
acidhydroxyethyl amide.
U.S. Pat. No. 3,557,280 discloses aqueous solutions of
oxytetracycline containing 1 to 20% oxytetracycline, a magnesium
compound and polyvinylpyrrolidone, 7.5 to 25%, at a pH of 8.0 to
9.5.
Belgian Pat. No. 825,656 discloses aqueous solutions of
oxytetracycline containing 4 to 11% oxytetracycline, 20 to 30% of a
polyethylene glycol, such as polyethylene glycol 400, a magnesium
compound and 0.10 to 0.35% of a buffer, such as
tris-(hydroxymethyl)-aminomethane at a pH of 8 to 9.
French Pat. Publication No. 2,258,187 discloses aqueous solutions
of oxytetracycline containing 50 mg./ml. of oxytetracycline, 5 to
7.49% polyvinylpyrrolidone and up to 24.9% of an acid amide
containing one to six carbon atoms, such as dimethylacetamide, at a
pH of 8 to 9.5.
SUMMARY OF THE INVENTION
It has now been found that stable high potency solutions of
oxytetracycline can be provided by means of a novel pharmaceutical
composition comprising a solution in water of from about 1 to 40%
by weight of an antibiotic compound selected from oxytetracycline
and the pharmaceutically acceptable acid addition salts thereof,
about 0.8 to 1.3 molar proportion of a pharmaceutically acceptable
magnesium compound soluble in said solution, and from about 10 to
50% by weight of 2-pyrrolidone, said composition having a pH value
in the range of from about 7.5 to 9.5.
DETAILED DESCRIPTION OF THE INVENTION
Oxytetracycline, the therapeutically-active component of this
invention, is a widely used tetracycline-type antibiotic. It is
particularly described in U.S. Pat. No. 2,516,080. An effective
concentration range for oxytetracycline in the solutions of this
invention is generally from about 1 to 40% by weight of the total
in the form of the free base or a pharmaceutically acceptable acid
addition salt. The preferred form is the free base with the
preferred concentration being from about 10 to 40% by weight, with
the especially preferred concentration being from about 20 to 30%
by weight.
Examples of suitable oxytetracycline acid addition salts which can
be used include such pharmaceutically acceptable acid addition
salts as the hydrochloride, hydrobromide, sulfate, nitrate,
ascorbate, citrate, gluconate, lactate, isonicotinate, gentisinate,
pantothenate, salicylate, glucuronate, formate and glutamate.
However, the preferred acid addition salt is oxytetracycline
hydrochloride.
Magnesium ions combine with oxytetracycline in solution to form
magnesium-oxytetracycline chelates. Magnesium oxide is a convenient
and preferred source of magnesium ions, but other magnesium
compounds useful for the purpose of this invention include
magnesium chloride, magnesium acetate, magnesium sulfate, magnesium
ascorbate, magnesium lactate and magnesium gluconate. The molar
ratio of magnesium to oxytetracycline in these compositions is
about from 0.8 to 1.3 mole of oxytetracycline. This ratio is
necessary to produce clear stable solutions. Suspended solids
remain in the solvent when introduction of less than 0.8 or more
than 1.3 moles of magnesium ion is used.
2-Pyrrolidone is present as a co-solvent in a concentration of from
about 10 to 50% based on the total weight of the composition.
2-Pyrrolidone is also known as 2-pyrrolidinone, 2-oxopyrrolidine,
.alpha.-pyrrolidone and 2-ketopyrrolidine. It has an ordal
LD.sub.50 of 8 gm/kg in rats and 3.8 gm/kg by intraperitoneal
injection in mice. Its use allows for minimum volume per dose and
excellent syringeability due to low viscosity of the resultant
composition.
As an optional ingredient polyvinylpyrrolidone having a molecular
weight of between about 5,000 and 100,000 (K-12 to 30) may also be
present in a concentration of from about 1 to 7% by weight. The
polyvinylpyrrolidone preferred for this invention is one having an
average molecular weight of about 10,000 - 17,000 (where K-value =
17). It is also present in part as a cosolubilizer and may improve
tissue toleration.
The stability of these solutions for therapeutic administration is
still further enchanced by the use of antioxidants such as sodium
or magnesium formaldehyde sulfoxylate at levels of from about 0.01
to 1.0% by weight.
The pH value is adjusted if necessary to pH 7.5 to 9.5. The
preferred range is pH 8.5 to 9.0. The pH can be adjusted with
organic bases such as aminoethanol, dimethlaminoethanol,
dimethylamine and so forth. Of these compounds, aminoethanol is the
preferred compound.
The compositions of this invention are readily prepared by mixing
the magnesium compound with the 2-pyrrolidone and water at about
75.degree. C and slowly adding the oxytetracycline antibiotic with
stirring until dissolved. The pH is then adjusted to the desired
range. If polyvinylpyrrolidone is to be included it is added to the
2-pyrrolidone and water before the addition of the magnesium
compound as previously described.
Oxytetracycline is currently available for parenteral
administration at a concentration of 50 mg./ml. Therefore a 500 Kg
steer would require 200 ml. of a 50 mg./ml. product injected into 5
to 10 different areas in order to receive an effective dose. The
compositions of this invention obviate this difficulty in that
easily syringable high dosage compositions are now possible, e.g.
200 mg./ml.
These compositions are also easy to syringe over a wide temperature
range, have acceptable animal tissue toleration, give therapeutic
blood levels and are satisfactory from a physical and chemical
stability standpoint.
The primary application is as a veterinary parenteral composition
but they can also be used for topical application.
______________________________________ gm/100 ml.
______________________________________ Oxytetracycline (based on a
potency 22.65 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
1.921 2-Pyrrolidone 40.00 Magnesium formaldehyde sulfoxylate 0.44
2-Aminoethanol 0.10 Water q.s. to 100 ml.
______________________________________
The 2-pyrrolidone was mixed with the water. The solution was heated
to about 75.degree. C and the magnesium formaldehyde sulfoxylate
was added and dissolved with stirring. The magnesium oxide was then
slurried with the solution. The oxytetracycline was slowly added
with stirring until a clear solution resulted. The solution was
allowed to cool to room temperature and the pH adjusted to 8.5 with
2-aminoethanol. The solution was then brought up to volume with
water.
The above solution containing 200 mg./ml. of oxytetracycline
activity had a viscosity of 13.0 cts. at 25.degree. C.
Tissue toleration was acceptable and blood levels were satisfactory
after subcutaneous injection in cattle.
The substitution of 1.0 gm. of sodium formaldehyde sulfoxylate for
the magnesium formaldehyde sulfoxylate produced a product similar
to the above.
______________________________________ mg./100 ml.
______________________________________ Oxytetracycline (based on a
potency 22.65 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
1.921 2-Pyrrolidone 40.00 Polyvinylpyrrolidone,K-17 5.00 Magnesium
formaldehyde sulfoxylate 0.44 2-Aminoethanol 0.17 Water q.s. to 100
ml. ______________________________________
The 2-pyrrolidone was mixed with water. Polyvinylpyrrolidone was
then added and stirred until dissolved. The procedure as described
in Example 1 was then followed.
The resulting product, containing 200 mg./ml. of oxytetracycline
activity, had a viscosity of 23 cts. at 25.degree. C.
Tissue toleration was acceptable and blood levels satisfactory
after subcutaneous and intramuscular injection in cattle.
The substitution of 1.0 gm. of sodium formaldehye sulfoxylate for
the magnesium formaldehyde sulfoxylate produced a product similar
to the above.
EXAMPLE 3
The following solution containing 25 mg./ml. of oxytetracycline
activity was prepared using the procedure described in Example
1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 2.831 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
0.245 2-Pyrrolidone 10.00 Sodium formaldehyde sulfoxylate 1.00
2-Aminoethanol 0.012 Water q.s. to 100 ml. The viscosity was 2 cts.
at 25.degree. C. ______________________________________
EXAMPLE 4
The following solution containing 50 mg./ml. of oxytetracycline
activity was prepared using the procedure described in Example
1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 5.662 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
0.490 2-Pyrrolidone 20.00 Sodium formaldehyde sulfoxylate 1.00
2-Aminoethanol 0.065 Water q.s. to 100 ml. The viscosity was 2.5
cts. at 25.degree. C. ______________________________________
EXAMPLE 5
A solution containing 100 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 11.325 of 927 .gamma./mg. plus a 5% overage) Magnesium
oxide 0.480 2-Pyrrolidone 35.00 Sodium formaldehyde sulfoxylate
1.00 Water q.s. to 100 ml. The viscosity was 3.0 cts. at 25.degree.
C. ______________________________________
EXAMPLE 6
The following solution containing 200 mg./ml. of oxytetracycline
activity was prepared using the procedure described in Example
2.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 22.65 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
1.421 2-Pyrrolidone 40.00 Polyvinylpyrrolidone,K-30 5.00 Magnesium
formaldehyde sulfoxylate 0.44 2-Aminoethanol 0.50 Water q.s. to 100
ml. The viscosity was 5.0 cts. at 25.degree. C.
______________________________________
EXAMPLE 7
A solution containing 200 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 2.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline
hydrochloride (based on 23.20 a potency of 905 .gamma./mg. plus a
5% overage) Magnesium oxide 1.921 2-Pyrrolidone 40.00
Polyvinylpyrrolidone,K-17 5.00 Magnesium formaldehyde sulfoxylate
0.44 2-Aminoethanol 3.84 Water q.s. to 100 ml. The viscosity was 45
cts. at 25.degree. C. ______________________________________
EXAMPLE 8
A solution containing 200 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 2.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 22.65 of 927 .gamma./mg. plus a 5% overage) Magnesium
chloride, hexahydrate 9.668 2-Pyrrolidone 40.00
Polyvinylpyrrolidone,K-17 5.00 Magnesium formaldehyde sulfoxylate
0.44 2-Aminoethanol 0.88 Water q.s. to 100 ml. The viscosity was 35
cts. at 25.degree. C. ______________________________________
The viscosity was 35 cts. at 25.degree. C.
EXAMPLE 9
The following solution containing 200 mg./ml. of oxytetracycline
activity was prepared using the procedure described in Example
1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 22.65 of 927 .gamma./mg. plus a 5% overage) Magnesium
acetate, tetrahydrate 10.021 2-Pyrrolidone 40.00 Sodium
formaldehyde sulfoxylate 1.00 2-Aminoethanol 0.76 Water q.s. to 100
ml. The viscosity was 33 cts. at 25.degree. C.
______________________________________
EXAMPLE 10
A solution containing 300 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 33.975 of 927 .gamma./mg. plus a 5% overage) Magnesium
oxide 2.94 2-Pyrrolidone 50.00 Sodium formaldehyde sulfoxylate 1.00
Water q.s. to 100 ml. The viscosity was 70 cts. at 25.degree. C.
______________________________________
EXAMPLE 11
A solution containing 350 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 39.597 of 927 .gamma./mg. plus a 5% overage) Magnesium
oxide 3.43 2-Pyrrolidone 50.00 Sodium formaldehyde sulfoxylate 1.00
Water q.s. to 100 ml. The viscosity was 200 cts. at 25.degree. C.
______________________________________
EXAMPLE 12
A solution containing 400 mg./ml. of oxytetracycline activity was
prepared using the procedure described in Example 1.
______________________________________ gm./100 ml.
______________________________________ Oxytetracycline (based on a
potency 45.30 of 927 .gamma./mg. plus a 5% overage) Magnesium oxide
3.92 2-Pyrrolidone 50.00 Sodium formaldehyde sulfoxylate 1.00 Water
q.s. to 100 ml. The viscosity was 785 cts. at 25.degree. C.
______________________________________
* * * * *